tbuckley/cabot-search huggingface dataset:
Abstract 362: <i>MYCN</i>-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis
Authors: Konstantinos V. Floros, Mia O. Johnson-Berro, Richard Kurupi, Carter K. Fairchild, Krista Dalton, Bin Hu, Madhavi Puchalapalli, Mikhail G. Dozmorov, Jennifer E. Koblinski, James A. Olzmann, Lauren A. Cowart, Anthony C. Faber
Journal: Cancer Research (2022)

Abstract MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Ferroptosis is an iron-dependent, oxidative form of cell death that is counteracted mainly by the production of Glutathione Peroxidase 4 (GPX4), a phospholipid hydroperoxidase that is produced through the glutathione pathway. The identification of cancers that may benefit from ferroptosis inducers are just emerging. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1 (TFR1). Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. By performing metabolomics, we demonstrate that the transsulfuration pathway is also activated by MYCN. The increased activation of both pathways leads to cysteine accumulation that results in inhibition of lipid peroxidation. Utilizing drugs that target the main components of the glutathione and transsulfuration pathway we sensitize the MYCN neuroblastomas to ferroptotic cell death. These data provide novel insights into how MYCN alters the transcriptome in neuroblastoma to confer growth and survival advantages and simultaneously sheds light on the mechanism of action of ferroptosis inducers with potential application in other types of cancer. Citation Format: Konstantinos V. Floros, Mia O. Johnson-Berro, Richard Kurupi, Carter K. Fairchild, Krista Dalton, Bin Hu, Madhavi Puchalapalli, Mikhail G. Dozmorov, Jennifer E. Koblinski, James A. Olzmann, Lauren A. Cowart, Anthony C. Faber. MYCN-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 362.
Abstract 510: Molecular subtypes related to prostate cancer disparities and disease outcome in African American and European American patients
Authors: Joakin Opeli Mori, Jason White, Balasubramanyam Karanam, Clayton Yates, Honghe Wang
Journal: Cancer Research (2022)

Abstract Prostate cancer disproportionately affects African American (AAM) men, yet present biomarkers do not factor in prostate cancer racial disparity. The objective of this study was to identify biomarkers with potential benefits to AAM prostate cancer patients. Differentially expressed genes (DEG) analysis coupled with gene set enrichment analysis (GSEA) and leading-edge genes analysis showed that the keratin family of genes, including KRT8, KRT15, KRT19, KRT34, and KRT80, constituted the single most prominent family of genes enriched in AAM compared to European American (EAM) prostate cancer cell lines. In prostate cancer patients (TCGA and MSKCC patient cohorts), only KRT8, KRT15, and KRT19 expression were relatively higher in AAM than in EAM. The differences in the expression of KRT15 and KRT19, but not KRT8, were enhanced by Gleason score and ERG fusion status; in low Gleason (Gleason ≤ 6 [TCGA cohort] and Gleason ≤ 7 [MSKCC cohort]), the expression of KRT15 and KRT19 was significantly (p ≤ 0.05) higher in AAM than in EAM patients. Survival analysis revealed that high expression of KRT15 and KRT19 was associated with increased risk of biochemical recurrence in low Gleason category patients in the TCGA patient cohort. Interestingly, KRT15 and KRT19 expression was associated with an increased risk of death in the metastatic prostate adenocarcinoma (SU2C/PCF Dream Team, PNAS 2019) cohort, suggesting the potential to predict the risks of disease recurrence and death in the low Gleason category and advanced disease conditions respectively. Gene set enrichment analysis revealed known oncogenic gene signatures, including KRAS and ERBB2, to be enriched in patients expressing high KRT15 and KRT19. Furthermore, high KRT15 and KRT19 were linked to the basal and LumA prostate cancer subtypes associated with poor postoperative androgen deprivation therapy (ADT) response compared to the LumB subtype. Taken together, the present study identifies genes with high expression in AAM than in EAM prostate cancer. The identified genes are linked to oncogenic gene signatures, including KRAS and ERBB2, and to basal and LumA prostate cancer subtypes that are associated with poor postoperative ADT response. The study, therefore, reveals biomarkers with the potential to address biomarker bias in prostate cancer diagnosis and/or prognosis. Future studies would explore the diagnostic and/or prognostic potential of identified markers in prostate cancer tissue samples. Citation Format: Joakin Opeli Mori, Jason White, Balasubramanyam Karanam, Clayton Yates, Honghe Wang. Molecular subtypes related to prostate cancer disparities and disease outcome in African American and European American patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 510.
Abstract 3862: Microbial immunomodulation for enhancing immunotherapeutic efficacy in a patient-specific colorectal cancer chip
Authors: Yong Cheol Shin, Alexander Wu, Soyoun Min, Daesung Kim, Woojung Shin, S. Gail Eckhardt, R. Y. Declan Fleming, Hyun Jung Kim
Journal: Cancer Research (2022)

Abstract Immune checkpoint inhibitors (ICI) targeting PD-1, PD-L1, or CTLA-4 have shown remarkable therapeutic outcomes in various cancers. However, the therapeutic efficacy of ICI-based immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC) has been extremely limited. Recent studies strikingly revealed that the human gut microbiome controls the efficacy of immune checkpoint blockades. Yet, the effect of the gut microbiome on reinforcing the ICI efficacy in MSS tumors in CRC is unknown. Here, we suggest a microengineered CRC Chip that recapitulates the tumor microenvironment of individual CRC patients by introducing biopsy-derived colonic organoid epithelium. We have built a three-dimensional (3D) lumen-capillary interface under peristalsis-like motions and flow in an oxygen-controlled microenvironment. We leverage this pathomimetic CRC Chip to recapitulate the patient-specific tumor-microbiome-immune axis to demonstrate microbial immunomodulation on the tumor cells and cytotoxic tumor immunity. We co-cultured various human intestinal bacteria in a CRC Chip to assess the immunomodulatory contribution to the tumor epithelium. We found that living Bifidobacterium sp. significantly reduces the PD-L1 on the tumor surface, followed by elevated anti-tumor activity after CD8 T cell-mediated cytotoxic interactions. We envision that our CRC Chip model can potentially reduce the knowledge gap between the bench and bedside. Furthermore, our innovative CRC Chip model may potentially offer a platform to validate the “Druggable microbiome” and the utility of the patient’s avatar model for Precision Medicine. Citation Format: Yong Cheol Shin, Alexander Wu, Soyoun Min, Daesung Kim, Woojung Shin, S. Gail Eckhardt, R. Y. Declan Fleming, Hyun Jung Kim. Microbial immunomodulation for enhancing immunotherapeutic efficacy in a patient-specific colorectal cancer chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3862.
Abstract 4178: PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer
Authors: Shengchen Su, Sungyong You, Yanping Wang, Patrick Tamukong, Catherine S. Grasso, Hyung L. Kim
Journal: Cancer Research (2022)

Abstract Prostate cancers have low immune infiltration and do not respond to PD1 blockade immunotherapy. The objective of this study was to examine the effect of PAK4 inhibition on anti-tumor immune response in preclinical prostate cancer models. C57BL/6J mice (male, 5-8 weeks old) were injected with wild type (WT) or PAK4 knockdown (KD) syngeneic Rm1 tumor cells (2X105 cell/mouse) and treated with or without αPD1 blockade (200μg, BioXCell). Tumor growth was monitored and analyzed using ANOVA of repeated measures (n=6). In a separate experiment, 1 cm RM1 tumors were collected for RNA sequencing (RNASeq) and immunohistochemistry (IHC). RNASeq data were normalized using the variance stabilizing transformation (VST) function as implemented within the DESeq2 package. IHC images were captured with Keyence BZ-X800 and positive staining was calculated using ImageJ. CD8+ lymphocytes depletion was achieved by CD8 antibody injection (200ug, BioXCell). PAK4 inhibitors PF-3758309 (PF) and KPT-9274 (KPT) were evaluated in murine models. PAK4 KD tumors treated with αPD1 antibody (αPD1) showed a significant reduction of tumor growth when compared to growth in WT (P&amp;lt;.05), WT αPD1 (P&amp;lt;.01), and KD (p&amp;lt;.05). Analysis of bulk tumor RNAseq showed that the combination of PAK4 KD with αPD1 was associated with increased CD8a, IFNγ, and PD-L1 expression. IHC with αCD8 verified that PAK4 KD increased CD8+ cell infiltration in mouse tumors. Further, RNAseq showed that PAK4 KD increased the expression of cytokines, chemokines, and genes related to the IFNγ response. These results suggest that PAK4 KD primes the tumor for immune infiltration and improves αPD1 treatment response. The anti-tumor effect of PAK4 KD with αPD1 in mice was CD8-dependent and could be eliminated by CD8+ cell depletion (p&amp;lt;.05). We tested two different PAK4 inhibitors in mice with WT Rm1 tumors. PF is a kinase inhibitor that blocks the function of PAK4. A combination of PF and αPD1 significantly reduced tumor growth when compared to WT (P&amp;lt;.05), WT αPD1 (P&amp;lt;.01), and PF (p&amp;lt;.05). KPT is a dual inhibitor of PAK4 and NAMPT, which reduces the cytosolic protein concentration of PAK4. A combination of KPT and αPD1 significantly reduced tumor growth when compared to WT (P&amp;lt;.01) and WT αPD1 (P&amp;lt;.01). In conclusion, PAK4 inhibition increased immune infiltration and improved αPD1 treatment response in preclinical mouse prostate cancer models. Citation Format: Shengchen Su, Sungyong You, Yanping Wang, Patrick Tamukong, Catherine S. Grasso, Hyung L. Kim. PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4178.
Abstract SY03-02: Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome
Authors: Paul S. Mischel
Journal: Cancer Research (2022)

Abstract Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA poses one of the greatest challenges for cancer patients, affecting children and adults and women and men, with a wide variety of cancer types. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. ecDNA, because of its non-chromosomal inheritance, drives high-copy number oncogene amplification and enables tumors to evolve their genomes rapidly, contributing to treatment resistance and shorter survival for patients. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription. In this talk, I will discuss recent collaborative discoveries that highlight how the higher order, spatial organization of ecDNA, and its mechanism of inheritance, contributes to aggressive tumorigenesis, accelerated evolution, and treatment resistance. Citation Format: Paul S. Mischel. Extrachromosomal DNA (ecDNA): Cancer's dynamic circular genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY03-02.
Effectiveness of a COVID-19 Testing Outreach Intervention for Latinx Communities
Authors: David S. DeGarmo, Stephanie De Anda, Camille C. Cioffi, Hannah F. Tavalire, Jacob A. Searcy, Elizabeth L. Budd, Ellen Hawley McWhirter, Anne Marie Mauricio, Sven Halvorson, Emily A. Beck, Llewellyn Fernandes, Mark C. Currey, Jorge Ramírez García, William A. Cresko, Leslie D. Leve
Journal: JAMA Network Open (2022)

Latinx individuals have been disproportionately affected during the COVID-19 pandemic caused by the spread of SARS-CoV-2. It is imperative to evaluate newly developed preventive interventions to assess their effect on COVID-19 health disparities.To examine the effectiveness of a culturally tailored outreach intervention designed to increase SARS-CoV-2 testing rates among Latinx populations.In this cluster randomized trial performed from February 1 to August 31, 2021, in community settings in 9 Oregon counties, 38 sites were randomized a priori (19 to the community health promoters intervention and 19 to outreach as usual wait-listed controls). Thirty-three sites were activated. A total of 394 SARS-CoV-2 testing events were held and 1851 diagnostic samples collected, of which 919 were from Latinx persons.A culturally informed outreach program was developed that made use of promotores de salud (community health promoters) to increase Latinx SARS-CoV-2 testing. Strategies addressed barriers by disseminating information on testing events in English and Spanish, mitigating misinformation, and increasing trust.The primary outcomes were the count of sample tests from Latinx persons and the sampled proportion of the Latinx populace. Site-level covariates included census tract Latinx populace, nativity (number of US-born individuals per 100 population), median age, and income inequality. Time-varying covariates included number of new weekly SARS-CoV-2-positive cases and percentage of vaccine coverage at the county level.A total of 15 clusters (sites) were randomized to the control group and 18 to the community health promoters group. A total of 1851 test samples were collected, of which 995 (53.8%) were from female participants and 919 (49.6%) were from Latinx individuals. The intervention tested 3.84 (95% CI, 2.47-5.97) times more Latinx individuals per event than controls (incident rate ratio, 0.79; 95% CI, 0.46-1.34; Cohen d = 0.74; P < .001). The intervention was associated with a 0.28 increase in the proportion of Latinx populace being tested compared with control sites for the dependent variable scaled as the proportion of the Latinx populace ×100, or a 0.003 proportion of the raw populace count. The use of a standardized scaling of the proportion of Latinx individuals showed that the relative percentage increase was 0.53 (95% CI, 0.21-0.86) in the intervention sites compared with controls, representing a medium effect size.To our knowledge, this was the first randomized evaluation of an outreach intervention designed to increase SARS-CoV-2 testing among Latinx populations. Findings could be used to implement strategies to reduce other health disparities experienced by these groups.ClinicalTrials.gov Identifier: NCT04793464.
Abstract PL01-03: From population to personalized prevention: Lessons from Barrett's esophagus
Authors: Rebecca Fitzgerald
Journal: Cancer Research (2022)

Abstract Cancer medicine is undergoing a radical shift away from a reactive approach in patients presenting with symptomatic disease towards a more proactive approach aimed at early diagnosis, including at the pre-cancerous stage. Oesophageal adenocarcinoma develops gradually from the pre-malignant condition Barrett’s oesophagus which presents an opportunity to radically improve outcomes from this highly aggressive cancer. Work to unravel the: clinical-demographic and inherited risk factors; the cell of origin of this disease; and the molecular landscape of Barrett’s samples over time and space, in patients with different outcomes, is shedding light on the disease pathogenesis. Our improved understanding of the disease can be used to develop novel approaches to risk-based population screening and personalised prevention. One emerging paradigm is a triage system that comprises a risk assessment, followed by targeted screening using novel non-endoscopic detection devices coupled with molecular biomarkers to identify individuals at high risk of invasive cancer needing monitoring or preventative treatment. In patients with a Barrett’s lesion undergoing monitoring, molecular strategies can further distinguish between those with indolent disease versus those likely to progress. As we redesign clinical pathways for this disease we must be sure to maximise patient and clinician acceptability, affordability and ease of access to a given technology while balancing the risks for over-diagnosis and over-treatment. Citation Format: Rebecca Fitzgerald. From population to personalized prevention: Lessons from Barrett's esophagus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL01-03.
Abstract 2672: ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models
Authors: Erin D. Lew, Joanne Oh, Taylor Congdon, Jingchuan Zhang, Robert F. Shoemaker
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) remains an unmet medical need where more than 50% off patients have tumors that are driven by somatic mutations in the RAS/MAPK signaling pathway. Targeted therapies, such as anti-EGFR inhibitors for patients with BRAFwt/RASwt CRC tumors and encorafenib + cetuximab for patients with BRAFV600E CRC tumors, are available treatment options but demonstrate both limited overall response rates and duration of response (Yaeger, 2018). In particular, in the previously treated setting, overall survival is typically less than a year (Grothey, 2013; Mayer, 2015; Kopetz, 2019). In addition, targeted treatment options are limited for patients harboring KRAS or NRAS mutations as emergence of these mutations is a predictive biomarker to anti-EGFR therapy resistance in metastatic CRC. ERAS-007 is a selective ERK1/2 inhibitor targeting the terminal node of the RAS/MAPK signaling pathway. In addition, ERAS-007 demonstrates single digit nanomolar biochemical ERK1/2 inhibition as well as a durable target residence time, thus making it a promising combination partner in RAS/MAPK pathway activated or altered CRC. To this end, ERAS-007 was evaluated in preclinical models in combination with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC. ERAS-007 demonstrated monotherapy activity and combination benefit in cell-based assays as well as superior combination efficacy in vivo relative to respective monotherapy control arms. In summary, ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination that support further exploration in the clinic. Accordingly, ERAS-007 combinations with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC are currently being evaluated in the HERKULES-3 phase 1b/2 master protocol (NCT05039177). Citation Format: Erin D. Lew, Joanne Oh, Taylor Congdon, Jingchuan Zhang, Robert F. Shoemaker. ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2672.
Abstract 2680: PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23
Authors: Matthew D. Gregory, Nada Tawfeeq, Jassy M. Lazarte, Yonghao Jin, Pablo Puente, Nadine Belony, Ite A. Offringa, Yong Huang, Nazarius S. Lamango
Journal: Cancer Research (2022)

Abstract Lung cancer is a leading cause of cancer-related mortality accounting for 23% of cancer deaths in the US. Non-small cell lung cancer (NSCLCs) comprises 84% of all lung cancer cases, and of these, 40% are lung adenocarcinoma (LUAD). Moreover, black Americans are underrepresented in scientific clinical trials but have a lung cancer incidence rate that is 37% higher than their white counterparts. To address this disparity and lack of effective treatment options, we determined the potency of polyisoprenylated cysteinyl amide inhibitors (PCAIs) on cell viability and its effects on KRAS and its downstream mediators in NCI-H23, a black American cell line that harbors a KRAS mutation. Among the 17 PCAIs that were tested, compound NSL-YHJ-2-27 showed the most potency with an EC50 of 2.7 µM. Western blot analysis was performed to determine the effect of the PCAIs on the levels of Mitogen-Activated Pathway Kinase (MAPK)-related proteins. After 48 h of exposure to 5 μM of NSL-YHJ-2-27, we observed increases of 150, 64.5, and 77% in phosphorylation levels of ERK1/2, MEK1/2, and 90RSK. While the particular 90RSK enzymes whose phosphorylation is/are elevated are not known at this time, 90RSK 3 and 4 are known to be proapoptotic. These findings suggest that the PCAIs may be used to target cancers with KRAS mutations that currently lack effective therapies. In the future, we will use a collection of isogenic cell lines to examine the potency of the PCAIs in LUAD driven by other RAS and related monomeric G-proteins, epidermal growth factors, and their receptors as well as RAS-GAPs. Therapies emanating from these studies have the potential to contribute to mitigating the lung cancer therapeutic inequities. Keywords: Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs), Mitogen Activated Pathway Kinases (MAPK), KRAS, Lung Adenocarcinoma (LUAD), Non-small cell lung cancer (NSCLCs) Citation Format: Matthew D. Gregory, Nada Tawfeeq, Jassy M. Lazarte, Yonghao Jin, Pablo Puente, Nadine Belony, Ite A. Offringa, Yong Huang, Nazarius S. Lamango. PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2680.